Greetings

 

My apologies for not getting this blog out earlier (time travel and jet lag)

 

What a great conference.  It has been great pleasure to meet many of the 2015 CROI ASHM bloggers.

 

There has been a lot of research and data looking at HIV infection and chronic systemic inflammation measured by an array of inflammatory biomarkers to predict HIV morbidity from cardiovascular disease, Neuro cognitive disease and cancers to name a few.  This research has highlighted the importance of HIV infection and the risk of HIV morbidities especially in older age groups and that predictive value of traditional markers in HIV infection such as CD4 and VL must be further evaluated.

 

To continue on this theme of HIV morbidity; Steven Grindspoon of Massachusetts General Hospital.

Presented cardiovascular disease in HIV patients – An emerging Paradigm and call to action

This plenary session presented that the understanding of current CVD risk in HIV is limited as are treatment preventions. Chronic inflammatory biomarkers can be used as predictive markers. HIV individuals at risk of CVD risk are not identified through traditional screening pathways. We should not forget the HIV drug combination and other factors such as smoking, body fat composition, type 2 diabetes, platelet dysfunction, endothelial, renal function that contribute to CVD.

 

HIV immune activation relates to novel atherosclerotic phenotype in HIV. It is therefore vital to identify these individuals who may be at risk of CVD. With the current CVD risk stratification many individuals would not receive recommendation for statin treatment under current guidelines.

 

It is known that statins decrease CVD events in non HIV patients with low LDL and raised CRP (LDL lowering and dampening immune activation)

 

Newer statins do not effect glucose and less likely to have drug interactions with ARVs. Pitavastatin is primarily metabolised by glucoronidation. Minimally metabolised by CYP3A which have very little drug interaction with ARVs and no dose reduction needed

REPRIEVE a RCT, looking at Pitavastatin versus placebo in asymptomatic HIV participants with a cardiac risk score of less than 7.5

 

Conclusion – Traditional and non tradition risk factors contribute to CVD, modulation of these factors needed. Atherosclerotic plaque formation in HIV positive individuals has unique pathophysiology and characteristics.  Significant challenges remain to identify at risk individuals and prevention strategies.

 

Cynthia Firnhaber presented a one year follow up cervical screening in HIV positive women in South Africa, this is significantly poignant as Cervical cancer is the highest cancer in women in Africa and responsible for 23% of all cancers. The risk of cervical cancer in HIV positive women is 3-6% higher than the general population.

 

In this cohort of 671 women 392, 92% were on ARVs, 80% were fully suppressed, average CD4.

 

Cynthia Furnhaber, University of Witswatersrand, Johannesburg, South Africa

One year follow up of HIV positive women, screen with VIA (visual inspection with
acetic acid), HPV and cytology

Cervical cancer is the leading cause of death in South Africa, with the risk of developing cervical cancer in HIV cancer 3-6 times the general population. In the WHO Africa region AFRO in 2012, 250,317 died of cancer (23% cervical cancer).

 

Screening for cervical cancer has proven preventable measure

1202 HIV positive women screen from a Johannesburg Clinic. All positive PAP smears and VIA had a colposcopy. Abnormal cervical areas got cryotherapy with CO2 or NO2.

837 women enrolled at baseline and 677 reviewed at one year. Characteristics such as age, CD4, VL, HPV were analysed separately.

Baseline 33% HSIL, 40%LSIL, 27% Normal a

One year follow up HSIL 7%, LSIL 70%, and Normal 23%

Average CD4 387, 87% VL< 1000, 93% ARVs

16% New HPV infection, 48% cleared HPV infection,

22% Progressed, 63% regressed via VIA

 

This study concluded that even HIV positive women who are on treatment have a significant risk of CIN progression and that cervical screening and access to healthcare is imperative to ensure gains in health for HIV positive women.

 

 

A eye opening plenary by Frances M Cowan, University College London, London, United Kingdom

The Price of Selling Sex: HIV Among Female Sex Workers—The Context and the Public Health Response

 

Globally female sex workers (FSW) are more 15% more likely to have HIV than general population. Meta-Analysis of the Burden of HIV in FSW –Asia 29% (countries not defined), Latin America 12%, Sub Saharan Africa 12% and modes of HIV transmission probably underestimate the effect of FSW in HIV transmission globally.

 

This talk then looked at prevention framework, legislation against violence against sex worker could reduce HIV transmission by 17-20% 0ver next decade, decrimalising sex work reduce HIV transmissions by 33-46% over the next decade.

 

Prevention framework should be through (individual, peers, community, public policy, and environment)

1)      Structural. Social justice and human rights.

2)      Behavioural

3)      Biomedical ART and Non ART

 

Implementation through social cohesion and safe space, collective power and sex worker participation.  (lubrication and condoms, STI treatment, HIV treatment, contraception, drug education, peer review, violence reduction and community empowerment.

Systemic review and met analysis of 22 studies and 33,000 FSW, showed a significant reduction in HIV, STIs (Gonorrhea, Chlamydia, Syphilis) and an increase in consistent condom usage with new and regular clients. Also discussed were newer biomedical interventions such as PrEP, PEP and HIV treatment to prevent MTCT.

 

WHO Guidelines - HIV diagnosis, treatment and care for key populations 2014

This talk focused on Sisters with a Voice  started in 2012 HIV and STI programme for FSW based at 5 sites in Zimbabwe –  Clinical services, health education, peer educators, community empowerment

24,000 women seen, 20,000 STI treatments, 7500 HIV tests, 3,200 HIV diagnoses and referred fro treatment. 1.4 million Condoms distributed (M) 96 000 (W) in 2014. 10 new HIV infections per 100 yrs follow up.

HIV prevalence in FSW in Zimbabwe 50-70%, minority are

SAPPIRE (Sisters Anti retroviral Programme for Prevention of HIV-an Integrated Response)

14 outreach sites in Zimbabwe, 200 FSW per site, 2800 in total

Random allocation of usual care sites to intervention sites

Usual care – (condoms, health education and HIV referral, Syndromic STI treatment, contraception, cervical screening and legal advice)

Intervention sites – (all usual care plus –HIV negative  HTC and PrEP, HIV positive – POC CD4 and onsite ART, community mobilisation – SMS and adherence support,  Adherence sisters programme.

 

Conclusions

Global epidemiology FSW 13.5 times higher risk of HIV than general population, effective HIV prevention and treatment programmes, novel biomedical approaches.

 Proper inclusion of sex workers and other key populations is essential to reach 90:90:90

 

The Thursday Afternoon Themed discussion  PEP- Remember me?

Kenneth H. Mayer

Fenway Health, Boston, MA, United States

 

Overview – Changes with PEP is transmission risk is one off event which needs prompt response with treatment, mostly conducted with animal studies and occupational studies, HIV transmission is relatively inefficient <1%. Guidelines are based on peer review studies. PEP guidelines vary with country to country even centre to centre.

Other options such as Behavioural/exposure/adherence, decrease host susceptibility, decrease source HIV infection

 

2014 WHO HIV PEP guidelines FOR Adults, adolescents and children 2014

PEP drugs 3> 2 is better

In adults and adolescents

-      2 ARVs is effective but evidence strength is low

-      TDF/3TC as preferred backbone evidence low- moderate

-      LPV/r or ATV/r as 3^rd drug Evidence very low (where available RAL, DRV/r, EFR considered as alternate options)

-      28 days good strength but evidence low

-      Adherence support conditional but evidence

Children

-      AZT/3TC preferred evidence low (ABC/3TC or TDF/FTC if available)

-      LPV/r (ATV/r/RAL/EFR/NVP) alternatives evidence low

-       

This looked at data from Tenofovir/Emtricitabine Plus LPV/r vs. MVC or Raltegravir for PEP: 2 Randomized Trials

Lorna Leal, Hospital Clinic Barcelona, Barcelona, Spain

 

Rilpivirine-Emtricitabine-Tenofovir for HIV No occupational Post exposure Prophylaxis

Rosalind Foster

Sydney Sexual Health Centre, Sydney, Australia

Significant Intolerability of Efavirenz in HIV Occupational Post exposure Prophylaxis

Surasak Wiboonchutikul

Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand

Management of Acute HIV After Initiation of Postexposure Prophylaxis: Challenges and Lessons Learnt

Goli Haidari

St Mary's Hospital–Imperial College Healthcare NHS Trust, London, United Kingdom

 

There were many good questions directed at the panel.

Drug tolerability and good adherence

Cost effectiveness and cost 2 drugs vs 3 drugs

No clear guidelines on HIV seroconversion during PEP

POC HIV tests  vs  4^th generation tests at baseline

Time to treatment similar to Occupational PEP

Genital tissue drug levels in men versus women - PrEP studies and long acting agents

This session concluded that there is very little evidence behind PEP especially with the newer drugs, WHO recommends 3 drugs  in PEP 2014 guidelines

Tolerability of drugs ( side effects and pill burden) impact on completion and adherence

More work is needed in this field

 

Greetings from CROI

 

High rate of HSIL on HRA in HIV positive women not meeting criteria for anal screening

 

Anal dysplasia in HIV positive women

 

Anal cancer is an uncommon cancer affecting 1.8 per 100000, although this figure is increasing in resource rich countries by 2% per year, the risk of developing anal cancer can be 10 times higher in HIV.

 

 

 

New York guidelines recommended that anal cytology should be taken at baseline and then annually in the following HIV-infected populations:

 

•Men who have sex with men

 

•Any patient with a history of anogenital condylomas

 

•Women with abnormal cervical/vulvar histology

 

Fanny Ita-Nagy presented a study from Icahn School of Medicine at Mount Sinai, New York

 

In this study from 2009 to 2014 they screened all HIV positive women who received care at the centre

 

Total number of women who had anal screening was 877. Out of this group 290 women were referred for high resolution anoscopy (HRA) due to high grade cytological changes.

 

Following HRA and anal biopsy 79 women had a histological diagnosis of HSIL and 1 woman had invasive anal squamous cell carcinoma.

 

In this study they also measured specific parameters, which included

 

Age, cervical intraepithelial neoplasia, genital warts, anal sex, smoking, HIV viral load, CD4 count.

 

This study concluded that 26% of the anal HSIL would have been missed if local anal screening guidelines had been followed.

 

Smoking was the only measured parameter that had a positive correlation with HSIL

 

This study recommended that the anal screening programme should be extended to all people living with HIV

 

HPV related high grade cervical and anal neoplasia have many parallels.

 

Take home message in Australia it is recommended that all HIV positive women should have an annual cervical PAP, although figures show that less than > 10% of HIV positive women who attended STI clinics actually underwent the recommended annual cervical PAP smear.

 

 Greetings from CROI

 

 Clinical pharmacology of HIV prevention- Marta Boffito (Chelsea and Westminster NHS Trust / Imperial College, London)

 

Marta Boffito presented a fascinating look at the pharmacology data of current drugs used in PrEP, the potential use of alternative drugs such as integrase inhibitors and CCR5 inhibitors and also data on the long acting nano technology of the future injectable drugs such as long acting Rilpiverine and Cabotegravir.

 

So what makes an ideal drug for PrEP?

• It needs to have good tissue distribution to achieve tissue drug levels
• It needs drug persistence (a long half-life)
• Protein binding affects penetration
• Affinity for transporter membranes

Tenofovir/FTC

 The data from large PrEP studies such as iPREX shows that Tenofovir/FTC achieved these targets when good adherence levels were achieved, however there was marked differences in drug levels in rectal samples compared to vaginal samples even with lower rates of adherence to the drugs in male group. This opens up some interesting questions on the optimal adherence needed for women to achieve adequate protective  vaginal drug levels.

 

CCR5 inhibitor

Maraviroc was looked at in men and women looking at serum samples, vaginal tissue and rectal tissue.  After only 2 hrs post standard dose of Maraviroc, protective drug levels were achieved in rectal and vaginal tissue samples. Rectal and vaginal drug levels were higher than serum levels( with x 30 times higher in rectal tissue than plasma).

 

Integrase inhibitors

Raltegravir - blood, vaginal and rectal samples. In vaginal fluid the half-life of standard dose of Raltegravir (400mg twice daily) was 17hrs compared to 7 hrs in blood sample. Both vaginal fluid and rectal samples had higher drug levels than found in blood samples. Drug levels  in rectal samples was higher than levels found in vaginal samples.

 

 Dolutegravir at standard dose, the drug levels in both vaginal and rectal samples were 10% and 17% higher than blood samples.

 

Long acting injectable drugs

 The SSAT040 study looked at drug levels in both vaginal and rectal tissue and fluid samples after a dose Rilpivirine (1200mg) from male and female participants. This study found that drug levels in the rectal samples were significantly higher than found plasma levels.

 Protective drug levels were found in both rectal and vaginal tissue at 1 month post treatment. It was also noted that lower drug levels were found in participants with a higher BMI.

 

In this study there was one case of drug failure and HIV transmission in a female participant at the lower Rilpivirine dose of 300mg. (the HIV transmission is thought to have occurred 4 days post dose).

 

After an initial dose of 1200mg Rilpivirine, drug levels in rectal tissue was found to be at  protective at four months.

 

Finally the long acting GSK 744 Cabotegravir at an 800mg dose found good serum drug levels at 4/12 months.

 

In an animal study, Macaques who received Cabotegravir as treatment sustained a viral suppression for up to 20 weeks post dose.

 

Conclusions

• Drug resistance to PrEP is rare.
• The debate of which drug is best is still out there.
• More work is required in this field to standardise intracellular drug concentrations.
• Ongoing debate on regular vs episodic PrE.

Take home message for current and future clinical practice.

Good clinical data on alternative and emerging drugs to be considered for PrEP. This interesting data also has valuable implications that may be applied for clinical use in non-occupational PEP use for CCR5 inhibitor and integrase inhibitors, where HIV transmission risk is significantly increased in the presence of multiple concurrent STIs.

 Greetings from CROI 2015

This is a big conference with a substantial focus on topics such PrEP programmes and Hepatitis C treatments. However I would like to write on the data looking at HIV pathogenesis and long term persistent systemic inflammation which contribute to increasing age related morbidity such as cancer and cardiovascular risks.

In current HIV care, age related HIV morbidities such as cardiovascular disease; cancers, neurocognitive and frailty not only have a huge impact on the patient but also on what the service can offer. It may impact the HIV drugs prescribed and the drug to drug interactions must be considered.  General practice and specialist HIV monitoring may need to be increased and multidisciplinary support for lifestyle modifications such as smoking cessation, diet, exercise etc.

Peter W Hunt of University of California convened and presented a workshop – Pathogenesis of HIV complications, which was an overview of HIV complications many of which present as HIV age related morbidities, immune modulated pathogenesis factors and the use of inflammatory bio markers.

What this session highlighted is the pathogenesis of HIV is complex with chronic inflammatory processes playing a significant role in the end organ disease. It also questioned if traditional HIV markers such as CD4 and VL have any predictive value for morbidity and illness such as cancer or cardiovascular events.

It is well documented that both primary HIV infection and chronic HIV infections have a direct and significant impact on the in the lymphatic system, especially when looking at the Gut Associated Lymphoid Tissue GALT. In this workshop it highlighted two pathways, firstly that persistent HIV infection and inflammation causes lymphoid tissue fibrosis, which changes the structure of lymphoid tissue and this in turn reduces lymphoid tissue availability for HIV naïve T cells and IL7 responses. A second suggested pathway is the HIV associated “leaky gut” which involves the lamina propria of the gut wall. This is a process effects the integrity of the gut immunity with specific depletion of T and B cells and disruption of the epithelial tight junctions, with impaired function and cytokine regulation.

In this overview workshop it presented a series of data looking at plasma inflammatory biomarkers (IL6 and D Dimer) in HIV positive individuals who were not on treatment, a second group who commenced treatment after longstanding HIV infection and a third group who started treatment early after primary HIV infection, these were compared to HIV negative control group. The IL6 and D dimer were markers were measured at baseline of treatment and subsequent follow up time intervals.

At baseline all HIV positive groups showed raised levels of IL6 and D dimer compared to controls. In the follow up of the second group (delayed HIV treatment), the levels improved but still remained elevated compared to the control group.  Interestingly for those individuals who commenced treatment soon after HIV diagnosis or during sero- conversion the D-Dimer and IL6 levels returned to a similar level as found in the HIV negative control group.

The take home message from this workshop is that the pathogenesis of HIV morbidity is complex and that a chronic persistent HIV with a chronic inflammatory immune response may contribute to the risk of developing HIV age related morbidity. Early HIV treatment is likely to have a positive impact on the process. Complex inflammatory markers have a role to play, but will not yet replace CD4, VL as the traditional markers for HIV management.

I would like to further blog on current research looking at persistent inflammation after initiation of HAART in acute HIV infection and HIV disease in the gut during acute HIV infection...